Benefits of Eliminating Cell Death Pathways in Health and Disease the underlying processes influencing vascular health remain largely undefined, leaving current therapeutic interventions to treat symptoms without a precise understanding the underlying, physiologically relevant disease and regenerative pathways. We propose to restrict inflammation and orchestrate repair and regeneration of hematopoietic and cardiovascular tissues by eliminating nonvital cell death and associated inflammatory processes. Our discovery that embryonic lethality of caspase 8 (Casp8)-deficiency in mice results from unleashed RIP3 necrosis opens the path to harnessing benefits of eliminating these pathways. Casp8-/- Rip3-/- (DKO) mice develop into viable and fertile adults that lack a susceptibility to inflammatory insult but retain sufficient immune function to control viral infection, prompting pilot efforts to harnes this setting to improve tissue repair, allogeneic engraftment and tissue regeneration. The Casp8 and RIP3 pathways evolved to counteract virus-encoded cell death suppressors, but become unleashed to cause inflammatory disease and undermine tissue repair, homeostasis and regeneration. This proposal employs genetic as well as small molecule approaches to eliminate cell death pathways, all modeled by DKO mice, as well as a additional mouse strains we have created. We have already shown that DKO mice resist acute inflammation, inflammatory cancer and ischemia reperfusion injury even though overall wound repair rates appear normal, prompting the very important question, How can benefit(s) from life in the absence of extrinsic cell death pathways be harnessed in the clinic? DKO cells engraft and differentiate with higher efficiencies than WT cells. Remarkably, Casp8-/-Rip3-/- mice survive allogeneic (MHC mismatched) bone marrow engraftment that causes acute graft versus host disease (GvHD) in WT C57BL/6 mice. Surprisingly, DKO fibroblasts support nuclear reprogramming with improved efficiency over WT cells. We propose to eliminate deleterious consequences of cell death through genetic manipulation, moving this area closer to a therapeutic intervention strategy to improve hematopoietic and cardiovascular tissue repair and regeneration. We propose to investigate genetic deficiency in mice and mouse cells, and develop knock-out strategies on rhesus macaque and human fibroblasts to combine with newly described small molecule inhibitors of RIP3 kinase and commercially available caspase inhibitors, to improve tissue repair, allogeneic transplantation and nuclear reprogramming. Our Aims are to: (1) optimize allogeneic engraftment, and (2) enhance nuclear reprogramming by eliminating extrinsic apoptosis without the disadvantage of triggering necrosis. The knowledge gained through these studies will have broad impact in current tissue repair and transplantation approaches, as well as future regenerative medicine strategies.